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IntroductionSchool-based social support for Black students may mediate or modify the association between school segregation and late-life cognition.MethodsStudy of Healthy Aging in African Americans participants (n = 574) reported segregated school attendance and school-based social support. Associations of segregated schooling with domain-specific cognitive outcomes and effect modification or mediation by school-based social support were evaluated with linear mixed models.ResultsSegregated school attendance was associated with increased likelihood of school-based social support. Segregated (vs. desegregated in 6th grade) school attendance was associated with lower executive function (β = -0.18 [-0.34, -0.02]) and semantic memory z-scores (β = -0.31 [-0.48, -0.13]). Social support did not mediate these associations. Estimates for segregated school attendance were attenuated among those who felt supported, although there was limited evidence of statistically significant effect modification.DiscussionEarly-childhood school segregation was associated with poorer cognitive function. Sources of resilience within racialized educational experiences should be further evaluated to bridge inequities.HighlightsSchool segregation is a form of structural racism that affected the educational experiences of Black youth with potentially lasting consequences for healthy brain aging. Black students who attended a segregated school experienced greater school-based social support, which may highlight a potential source of resilience and resistance against the effects of racism-related stressors on cognitive function. The estimated adverse association between attending a segregated school on cognition was larger for students without an adult at school who cared about them versus those with an adult at school who cared about them, but estimates were imprecise.

INTRODUCTION: Adopting healthy lifestyle behaviors has the potential to slow cognitive decline in older adults by reducing risks associated with dementia. Curriculum-based group health coaching may aid in establishing behavior change centered for dementia risk factors. METHODS: In this pilot clinical care patient group study (n = 6), we examined the effects of a six-month online Cognitive Health Program combined with a weekly telehealth support group led by the course creator, and personalized health optimization by a collaborating physician, in older adults with subjective cognitive decline. Cognition was assessed at baseline and post-intervention using a computerized battery. RESULTS: Cognitive changes were estimated with nonparametric tests and effect sizes (Cohens d). Results showed significant improvements in global cognition (p < 0.03, d = 1.6), spatial planning (p < 0.01, d = 2.3), and visuospatial processing (p < 0.05, d = 1.1) compared to baseline. Participants reported high levels of satisfaction with the virtual group format and online curriculum. CONCLUSIONS: This small pilot study suggests that a virtual six-month personalized health coaching group with self-paced online health education is feasible and potentially efficacious for improving cognition in participants with subjective cognitive complaints. This format may facilitate behavior change to slow cognitive decline. Future studies should include a control group, a larger, more diverse sample as well as assessing mood and other subjective measures.

microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer's disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables. Among these, 137 miRNAs remained differentially expressed after additionally adjusting for several co-occurring age-related cerebral pathologies, suggesting that some miRNAs are associated with the traits through co-occurring pathologies while others through mechanisms independent from pathologies. Pathway enrichment analysis of downstream targets of these differentially expressed miRNAs found enrichment in transcription, postsynaptic signalling, cellular senescence, and lipoproteins. In sex-stratified analyses, five miRNAs showed sex-biased differential expression for one or more AD endophenotypes, highlighting the role that sex has in AD. Lastly, we used Mendelian randomization to test whether the identified differentially expressed miRNAs contribute to the cause or are the consequence of the traits. Remarkably, 15 differentially expressed miRNAs had evidence consistent with a causal role, laying the groundwork for future mechanistic studies of miRNAs in AD and its endophenotypes.

BACKGROUND: Converging evidence suggests that markers of Alzheimers disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimers disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes. OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay. DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aβ+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aβ-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia. PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ- were enrolled into the LEARN Study (n=553). MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo). RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aβ- and A4 Aβ+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models. CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

BackgroundHypertension can have deleterious effects on cognitive function; however, few studies have examined its effects on cognition among Hispanics/Latinos.ObjectiveTo assess associations between hypertension status with 1) change in cognitive performance, and 2) having mild cognitive impairment (MCI) among diverse Hispanics/Latinos.MethodsThis population-based, prospective cohort, multisite study included Hispanic/Latino adults aged 45 to 72 years in enrolled in the Hispanic Community Health Study/Study of Latinos at Visit 1 (2008-2011; mean age of 63.40±8.24 years), and the Study of Latinos-Investigation of Neurocognitive Aging at Visit 2 (2016-2018), with a mean follow-up duration of 7 years (n = 6,173). Hypertension status was assessed at both visits: normotension (no hypertension), incident hypertension (only at Visit 2), and persistent hypertension (at both visits). We examined change in cognitive performance and having MCI (only assessed at Visit 2) relative to hypertension status and adjusted for demographics and cardiovascular disease risk factors.ResultsCompared to normotension, persistent hypertension was associated with significantly increased decline in verbal fluency (β= -0.08; CI = [-0.16;-0.01]; p

BackgroundAlzheimer's disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM).MethodsSGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years).ResultsPatients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition.ConclusionsThese results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.

BACKGROUND AND OBJECTIVES: Prior studies on cognitive reserve (CR) and cognitive trajectories are limited and have had conflicting results. Furthermore, most studies have used a single measure of CR that may not reflect a comprehensive exposure. The objective of this study is to determine the impact of individual and composite CR measures on cognitive decline over a 6-year period. RESEARCH DESIGN AND METHODS: We studied 55,340 participants from 16 European countries, aged 50 and older, who participated in the Survey of Health, Aging, and Retirement in Europe. We used cognitive measures (including immediate memory, delayed memory, verbal fluency, and numeracy) and 3 CR factors (education, occupation, and cognitive activities) collected in 4 waves from 2011 to 2017. Structural equation modeling was used to construct the composite CR score, analyzed as tertile. Linear mixed-effect models were used to examine the study aims. RESULTS: At baseline, the highest composite CR tertile was associated with a higher cognition score than the middle and lowest CR tertiles (β: -0.28, 95% confidence interval [CI]: -0.29 to -0.26; β: -0.71, 95% CI: -0.72 to -0.70, respectively), as well as for all individual cognitive domains. At longitudinal results, compared with the lowest CR, the highest but not the middle CR tertile demonstrated a slower 6-year decline in global cognition (β: -0.02, 95 % CI: -0.03 to -0.01), as well as in all cognitive domains (p

IntroductionThe prevalence of poor sleep quality and sleep apnea differs by race and ethnicity and may contribute to racial disparities in cognitive aging. We investigated whether sleep quality and sleep apnea risk were associated with cognitive function and decline and whether the associations differed by race/ethnicity.MethodsParticipants from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE; N = 1690; mean age: 75.7 years) study, a cohort of Asian, Black, Latino, and White participants, completed a modified Pittsburgh Sleep Quality Index assessing subjective sleep quality, latency, duration, disturbances, sleep medication use, and daytime dysfunction. Sleep apnea risk was measured by questions about snoring, tiredness, and whether apnea was observed. Executive function and verbal episodic memory were assessed at three time points over an average of 2.7 years with the Spanish and English Neuropsychological Assessment Scale. We fit linear mixed-effect models and stratified analyses by race/ethnicity.ResultsHigher sleep apnea risk was associated with faster declines in verbal episodic memory (β^ sleep apnea = -0.02, 95% confidence interval [CI], -0.04, -0.001) but not in executive function. Poorer sleep quality was associated with lower levels of and faster decline in executive function but not in verbal episodic memory. Race/ethnicity modified these associations: compared to estimated effects among White participants, poorer global sleep quality (β^ sleep*time = -0.02, 95% CI, -0.02, -0.01) was associated with larger effects on decline in executive function among Black participants. Estimated effects of some individual sleep quality components were also modified by race/ethnicity; for example, sleep medication use was associated with faster declines in executive function (β^ sleep*time = -0.05, 95% CI, -0.07, -0.03) and verbal episodic memory β^ sleep*time = -0.04, 95% CI, -0.07, -0.02) among Black participants compared to White participants.DiscussionObservational evidence indicates sleep quality is a promising target for addressing racial/ethnic disparities in cognitive aging, especially among Black older adults.HighlightsSleep apnea risk was associated with faster declines in verbal episodic memory but not executive function among all participants.Global sleep quality was associated with lower levels of and faster decline in executive function but not verbal episodic memory among all participants.Black older adults were particularly susceptible to the estimated adverse cognitive impacts of global sleep quality, particularly the use of sleep medication.

INTRODUCTION: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimers disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. METHODS: T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. RESULTS: Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. DISCUSSION: The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

Background: The role of Vascular risk factors (VRFs) in the progression of Alzheimer's Disease (AD) and cognitive decline remains to be elucidated, with previous studies resulting in conflicting findings. The possible impact of age-specific mechanisms of resilience/vulnerability is an under addressed issue. We evaluated the association of VRFs with markers of amyloid deposition, neurodegeneration, and blood-brain-barrier (BBB) permeability (Albumin quotient, Qalb), stratifying patients into early-onset (< 65, EOAD), classic late-onset (65–75, cLOAD) and very late-onset (> 75, vLOAD), to evaluate the moderating effect of age of onset. Moreover, we explored the effects of VRFs on cognitive decline at one year follow-up (ΔMMSE). Methods: For 368 patients with biologically confirmed AD, we computed eight risk factors in a composite measure of cumulative vascular risk (vascular score, VS). Stratifying patients according to age of onset, we regressed VS and main individual VRFs on p-tau/Aβ42, t-tau and Qalb, and used bootstrapped mediation analysis to test direct and indirect associations of VS with t-tau, using Qalb as mediator. In a subset of 105 patients, we performed multivariate backward regressions to assess the effects of sex, APOE, Qalb, VS, p-tau/Aβ42 and t-tau on ΔMMSE. Results: VS was positively associated with CSF t-tau in more vulnerable groups burdened by more aggressive disease progression (EOAD: β = 0.256, p = 0.019) or aging (vLOAD: β = 0.007, p < 0.001). Conversely, in patients with classic age of onset VS was associated with higher BBB permeability (cLOAD: β = 0.173, p = 0.015), which simultaneously causes the decrease of CSF t-tau, as a possible resilience response. Cognitive decline was not associated with VS in any of the subgroups. Instead, it was affected by both higher CSF t-tau and increased Qalb values in those with very early or very late onset (EOAD and vLOAD), but by Qalb alone in patients with classic age of onset, where CSF t-tau levels might be buffered by BBB permeability. Conclusions: Our results show that age of onset weighs on the heterogeneous effects played by VRFs in AD, which do not seem to have direct impact on cognitive decline. These findings stress the importance of a tailored patient-centered approach to the application of vascular prevention strategies in AD. [ABSTRACT FROM AUTHOR]

Dementia, especially Alzheimer's disease, presents a major clinical challenge, and researchers are still searching for an optimal animal model. To address this gap, we compared male and ovariectomized female C57BL/6 mice treated with 30 mg/kg aftin-4, which induces neurodegeneration, with naturally aged (15–16 months old) mice not treated with aftin-4. We performed a series of behavioral tests; measured postmortem plasma β-amyloid levels (Aβ1–40 and Aβ1–42) and the levels of the oxidative stress indicators glutathione peroxidase (GPx), superoxide dismutase (SOD) and malondialdehyde (MDA); and evaluated astrocytic reactivity in the brain using glial fibrillary acid protein (GFAP) levels. Our results revealed no behavioral changes in the aged or aftin-4-treated mice compared with the control mice. Aftin-4 mice presented lower brain MDA levels and no detectable changes in plasma Aβ levels. In general, female mice had higher GPx and SOD levels and lower Aβ1–42 levels than male mice did. In contrast, aged and aftin-4-treated male mice presented elevated levels of GFAP, indicating astrocyte damage. Our results could not confirm that either aftin-4-treated or aged mice are reliable models for dementia. However, the observed molecular changes suggest that male animals may be more susceptible to oxidative stress and brain damage than females are. This study demonstrates the complexity of modeling dementia in animals and the importance of future studies in this area. [ABSTRACT FROM AUTHOR]

The neurocognitive and psychiatric effects of Cushing's syndrome (CS) are well recognized and negatively impact quality of life. The aim of this systematic review is to compare neurocognitive disease, psychiatric symptoms, and structural brain changes in patients with Cushing's disease (CD)/CS and those with non‐functioning pituitary adenoma (NFPA), both before and after surgical treatment, and in comparison to healthy controls. Possible predictors of persistent neurocognitive symptoms and reduced quality of life in patients with CS are highlighted. We reviewed the English literature published in Medline/Pubmed until 2021 to identify eligible studies. This systematic review was registered on Prospero and reported following the PRISMA statement guidelines. The initial literature search yielded 1772 articles, of which 1096 articles remained after removing duplicates. After excluding case reports, animal studies, narrative reviews, comparative reviews, and articles not in English, 86 papers underwent full‐text review. Studies eligible for inclusion met the following criteria: (1) described patients with CD/CS, (2) reports of psychiatric symptoms, (3) written in English or with available English translation, and (4) published in a peer‐reviewed journal. The full‐text review process identified 40 eligible studies. The 40 studies included a total of 2603 participants with CD or CS, with 45.2% of the total participants having CD. The majority of studies were case–control studies and used validated questionnaires such as the Beck's Depression Index, Trail Making Test, Hospital Anxiety and Depression Scale, and Cushing Quality of Life for screening. Compared to NFPA controls, patients with CD who had greater baseline serum cortisol levels had worse cognitive function, even after surgical remission. This suggests a possible association between greater baseline cortisol levels in patients with CS and persistent cognitive impairment. A longer duration of uncontrolled CS was associated with worse cognitive function; however, there was no association found between the length of remission and memory. Overall brain volume was increased in patients in remission from CD compared to active disease. However, temporal and frontal lobe volumes did not recover to normal volumes. Patients with CS experience neurocognitive dysfunction, psychiatric disorders, and diminished quality of life, and symptoms may persist after curative surgery. We found several factors consistently associated with persistent cognitive and neuropsychiatric symptoms in patients with CS including higher pre‐operatively baseline cortisol production, longer duration of disease, frontal and temporal lobe atrophy, and the presence of cognitive and neuropsychiatric symptoms at baseline. Larger prospective studies are required to validate these findings. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes mellitus (T2DM) over time predisposes to inflammatory responses and abnormalities in functional brain networks that damage learning, memory, or executive function. The hippocampus is a key region often reporting connectivity abnormalities in memory disorders. Here, we investigated peripheral inflammatory responses and resting-state functional connectivity (RSFC) changes characterized of hippocampal subregions in type 2 diabetes-associated cognitive decline (T2DACD). Methods: The study included 16 patients with T2DM, 16 patients with T2DACD and 25 healthy controls (HCs). Subjects were assessed for cognitive performance, tested for the expression of inflammatory factors IL-6, IL-10 and TNF-α in peripheral serum, underwent resting-state functional magnetic resonance imaging scans, and analyzed for RSFC using the hippocampal subregions as seeds. We also calculated the correlation between cognitive performance and RSFC of hippocampal subregion, and analyzed the significantly altered RSFC values of T2DACD for Receiver Operating Characteristic (ROC) analysis. Results: T2DACD patients showed a decline in their ability to complete cognitive assessment scales and experimental paradigms, and T2DM did not show abnormal cognitive performance. IL-6 expression was increased in peripheral serum in both T2DACD and T2DM. Compared with HCs, T2DACD showed abnormalities RSFC of the left anterior hippocampus with left precentral gyrus and left angular gyrus. T2DM showed abnormalities RSFC of the left middle hippocampus with right medial frontal gyrus, right anterior and middle hippocampus with left precuneus, left anterior hippocampus with right precuneus and right posterior middle temporal gyrus. Compared with T2DM, T2DACD showed abnormalities RSFC of the left posterior hippocampus and right middle hippocampus with left precuneus. In addition, RSFC in the left posterior hippocampus with left precuneus of T2DACD was positively correlated with Flanker conflict response time (r=0.766, P =0.001). In the ROC analysis, the significantly altered RSFC values of T2DACD achieved significant performance. Conclusions: T2DACD showed a significant decrease in attentional inhibition and working memory, peripheral pro-inflammatory response increased, and abnormalities RSFC of the hippocampal subregions with default mode network and sensory-motor network. T2DM did not show a significant cognitive decline, but peripheral pro-inflammatory response increased and abnormalities RSFC of the hippocampus subregions occurred in the brain. In addition, the left precuneus may be a key brain region in the conversion of T2DM to T2DACD. The results of this study may provide a basis for the preliminary diagnosis of T2DACD. [ABSTRACT FROM AUTHOR]

Secondhand smoking may contribute to cognitive decline, but evidence on this subject is limited in the working economically active older adults. This study aimed to investigate the association between cognitive decline and exposure to secondhand smoke at work in economically active adults aged 65 years or above. Cross-sectional study using nationwide data. Data were from the 2022 Korea Community Health Survey. Chi-squared test was used to perform descriptive statistics. The association between cognitive decline and exposure to secondhand smoke at work was analysed using multivariable logistic regression analysis. Subgroup analysis was performed based on to exposure status to secondhand smoke at home and diabetes mellitus. Of a total of 28,197 adults, 8767 (28.5%) individuals reported cognitive decline. Compared to individuals without exposure to passive smoking at work, those with such exposure were more likely to report cognitive decline (odds ratio: 1.30, 95% confidence interval: 1.14–1.47). This association was particularly strong in individuals with exposure to passive smoking at both work and home and in those diagnosed with diabetes mellitus. Exposure to secondhand smoking at work is associated with a higher likelihood of cognitive decline in older-aged economically active individuals. The findings infer the importance of monitoring passive smoking and implementing public health measures to reduce workplace secondhand smoke exposure. [ABSTRACT FROM AUTHOR]

Cognitive decline is becoming more prevalent as population ages. Technology offers solutions to help people with cognitive decline age in place. A compassionate approach to care can promote engagement in technology use by older adults with cognitive decline and equitable access. This scoping review summarized research literature on approaches to design and selection of technology that could support a compassionate approach to technology use for daily functioning among adults with cognitive decline and their care partners. We used the framework of Arksey and O'Malley. Key words capturing constructs of compassion, technology, and cognitive decline were searched in CINAHL, Medline, and PsycINFO. Peer-reviewed articles about the design for or use of technology by persons with cognitive decline or their care partners were included. Two reviewers screened and extracted data. Data informing compassionate technology use were analysed thematically. Fifty-five included articles represented a variety of technologies and purposes with ethics being the predominant perspective (n = 15). Analysis identified four categories: 1) Person- and care partner-centered approach, 2) Tailoring design to abilities, 3) Tailoring selection and application, and 4) Training and support. Using study findings, we developed a framework for compassionate use of technology for people living with cognitive decline and their care partners. IMPLICATIONS FOR REHABILITATION: Compassionate approach to technology design and selection for person with cognitive decline and their care partners involves supporting autonomy, and consideration of ethical issues and specific technology purpose A family-centered care with a strong relational component is important when selecting technology with people with cognitive decline Healthcare providers and industry representatives require training to understand and adapt their approach to meet the needs of individuals living with cognitive decline and their care partners. [ABSTRACT FROM AUTHOR]

Introduction: Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. Methods: A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 (C9orf72) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. Results: For the ALS group, the statistical model explained 38.8% of variance in ECAS total (p < 0.001), 59.4% of executive functions (p < 0.001), and 55% of behavioral symptoms (p < 0.001). For controls, it accounted for 52.8% of variance in ECAS total (p < 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups (p < 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls (p = 0.004), and the gene mutation C9orf72 was found to be a behavioral symptom' predictor in patients (p = 0.009). Conclusion: This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive neurodegenerative pathology that leads to cognitive decline and dementia, particularly in older adults. It disrupts brain structure and function, with neurotoxic amyloid-β (Aβ) plaques being a primary pathological hallmark. Pharmacotherapeutic trials targeting Aβ and other AD pathological features aim to slow disease progression. Functional magnetic resonance imaging (fMRI) is a non-invasive tool that visualizes brain functional activity, aiding in evaluating the efficacy of AD drugs in clinical trials. Objective: This mini-review explores the role of fMRI in evaluating the impact of AD pharmacotherapeutic clinical trials conducted in the past seven years. Methods: Literature was systematically searched using two databases. The risk of bias was assessed with the Revised Cochrane risk-of-bias tool (RoB-2) for randomized clinical trials (RCTs). Results: Four studies using fMRI to investigate AD drug efficacy were included. Cholinesterase, glutamatergic, and serotonergic drugs showed significant positive effects on brain functional activity, especially within the default mode network. Functional connectivity (FC) changes due to drug intake were linked to cerebellar and cholinergic decline in AD, correlating with improved global cognition and fMRI task performance. Conclusions: Recent RCTs demonstrate fMRI's ability to reveal longitudinal FC pattern changes in response to AD drug treatments across disease stages. Positive FC changes in distinct brain regions suggest potential compensatory mechanisms from drug intake. However, these drugs have limited efficacy, necessitating further research to enhance specific pharmacological interventions for clinical application. [ABSTRACT FROM AUTHOR]

Dual decline in gait and cognition is associated with an increased risk of dementia, with combined gait and memory decline exhibiting the strongest association. To better understand the underlying pathology, we investigated the associations of baseline brain structure with dual decliners using three serial gait speed and cognitive assessments in memory, processing speed-attention, and verbal fluency. Participants (n=267) were categorized based on annual decline in gait speed and cognitive measures. Lower gray and white matter volume and higher white matter hyperintensity volume increased the risk of being a dual decliner in gait and both the memory and processing speed-attention groups (all p < 0.05). Lower hippocampal volume (p = 0.047) was only associated with dual decline in gait and memory group. No brain structures were correlated with dual decline in gait and verbal fluency. These results suggest that neurodegenerative pathology and white matter hyperintensities are involved in dual decline in gait and both memory and processing speed-attention. Smaller hippocampal volume may only contribute to dual decline in gait and memory. • Dual decline in gait and memory captures a range of underlying pathologies. • No brain structures were associated with dual decline in gait and verbal fluency. • Smaller hippocampal volume may only contribute to dual decline in gait and memory. [ABSTRACT FROM AUTHOR]

Depression has been found to be associated with cognitive decline, but whether longer depressive durations lead to more severe cognitive declines has not been investigated. We aimed to estimate the association between depressive duration and cognitive decline in middle-aged and older Americans based on a large-scale representative population study. We included 27,886 participants from the Health and Retirement Study (HRS) in 2010–2018. Four datasets with 2-, 4-, 6-, and 8-year consecutive interviews were further derived which involving persistent depressed and persistent depression-free individuals. Multiple linear regressions were constructed to estimate the effects of each depressive duration on the decline in global cognition, memory and mental status. Meta-regressions were performed to test the linear trends and to explore the heterogeneity between sex, age and baseline cognitive function along with subgroup analyses. Depressive durations of 2, 4, 6, and 8 years were associated with reductions in global cognitive scores of 0.62 points (95% CI: 0.51–0.73), 0.77 points (95% CI: 0.60–0.94), 0.83 points (95% CI: 0.55–1.10), and 1.09 points (95% CI: 0.63–1.55), respectively, indicating a linear trend (P = 0.016). More pronounced associations were observed in middle-aged adults and females. Similar patterns were found in the associations between depressive duration and two subdomains, i.e., memory and mental health. This study is essentially a cross-sectional study and therefore cannot provide causal associations. Longer depressive durations were linearly related to more severe cognitive declines. Timely intervention for depression targeted middle-aged adults can more effectively alleviate cognition-related burdens. • This is the first study focusing on the association between depressive duration and cognition based on a large population. • Depressive durations were linearly associated with declines in global cognition, memory and mental status. • Significant linear trends between depressive duration and cognitive function persisted in females and adults aged 51-65. • Considering depressive duration, middle-aged adults showed greater cognitive decline due to depression than older adults. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The potential utility of subjective cognitive decline (SCD) as an early risk marker of Alzheimer's disease and related dementias is under consideration. We examined associations between SCD and cognitive change among middle‐aged and older Hispanic/Latino adults living in the United States. METHODS: The short‐form Everyday Cognition Scale (ECog‐12) was assessed to generate global, executive function, and memory‐related SCD scores. We used survey generalized regressions to model the change in learning, memory, verbal fluency, executive function, and global cognitive performance over 7 years as a function of SCD (at Visit 2). RESULTS: The mean age was 56.37 ± 8.10 years at Visit 1 (n = 6225). Higher ECog‐12 was associated with greater decline in global cognitive performance (ECog‐12 global: B = –0.17, standard error [SE] = 0.02; ECog‐12 executive: B = –0.15, SE = 0.02; ECog‐12 memory: B = –0.14, SE = 0.02, p's < 0.001). DISCUSSION: These results support the link between subjective reports of cognitive decline and objectively measured 7‐year cognitive decline in community‐dwelling, middle‐aged, and older Hispanic/Latino adults. Highlights: We found that nearly two‐thirds of diverse middle‐aged and older Hispanics/Latinos reported cognitive concerns in a large and representative population study.Self‐reported subjective experiences of cognitive decline reflect objective cognitive decline in US Hispanics/Latinos.The relationship is stronger among men compared to women.The relationship between subjective and objective changes to memory are stronger in those with cognitive concerns, and remain even in cognitively healthy individuals. [ABSTRACT FROM AUTHOR]

INTRODUCTION: MicroRNAs are short non‐coding RNAs that control proteostasis at the systems level and are emerging as potential prognostic and diagnostic biomarkers for Alzheimer's disease (AD). METHODS: We performed small RNA sequencing on plasma samples from 847 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. RESULTS: We identified microRNA signatures that correlate with AD diagnoses and help predict the conversion from mild cognitive impairment (MCI) to AD. DISCUSSION: Our data demonstrate that plasma microRNA signatures can be used to not only diagnose MCI, but also, critically, predict the conversion from MCI to AD. Moreover, combined with neuropsychological testing, plasma microRNAome evaluation helps predict MCI to AD conversion. These findings are of considerable public interest because they provide a path toward reducing indiscriminate utilization of costly and invasive testing by defining the at‐risk segment of the aging population. Highlights: We provide the first analysis of the plasma microRNAome for the ADNI study.The levels of several microRNAs can be used as biomarkers for the prediction of conversion from MCI to AD.Adding the evaluation of plasma microRNA levels to neuropsychological testing in a clinical setting increases the accuracy of MCI to AD conversion prediction. [ABSTRACT FROM AUTHOR]

Dysregulation of G9a, a histone-lysine N-methyltransferase, has been observed in Alzheimer's disease and has been correlated with increased levels of chronic inflammation and oxidative stress. Likewise, microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis, especially in multifactorial diseases such as Alzheimer's disease. Therefore, our aim has been to provide partial insights into the interconnection between G9a, microRNAs, oxidative stress, and neuroinflammation. To better understand the biology of G9a, we compared the global microRNA expression between senescence-accelerated mouse-prone 8 (SAMP8) control mice and SAMP8 treated with G9a inhibitor UNC0642. We found a downregulation of miR-128 after a G9a inhibition treatment, which interestingly binds to the 3′ untranslated region (3′-UTR) of peroxisome-proliferator activator receptor γ (PPARG) mRNA. Accordingly, Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group. We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor. To confirm these antioxidant effects, we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult. In this setting, treatment with G9a inhibitor increases both cell survival and antioxidant enzymes. Moreover, up-regulation of PPARγ by G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis. In addition, we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression. Finally, PPARγ/GADD45α potentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition. Altogether, we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due, at least in part, by the modulation of PPARγ-dependent pathways by miR-128. [ABSTRACT FROM AUTHOR]

Background/Objectives: Hypomagnesemia and hypocalcemia are common conditions among older adults that may contribute to cognitive decline. However, most of the existing research has focused primarily on dietary intake rather than the actual serum levels of these nutrients or examined them separately. This study aims to investigate the relationship between hypomagnesemia, hypocalcemia, and the concurrent presence of both deficiencies in relation to cognitive performance among seniors. Methods: A total of 1220 hospitalized patients aged 60 and older were included in the analysis. The participants were categorized into four groups: those with normal serum levels of magnesium and calcium, those with hypomagnesemia, those with hypocalcemia, and those with both serum magnesium and calcium deficiencies. To evaluate the potential influence of age, sex, common comorbidities, and disturbances in magnesium and calcium levels on cognitive performance, two general linear models were employed, using the Mini-Mental State Examination (MMSE) and Clock-Drawing Test (CDT) as dependent variables. Results: After adjusting for age, sex, body mass index, and comorbidities, the mean values for the MMSE and CDT were 23.33 (95%CI: 22.89–23.79) and 5.56 (95%CI: 5.29–5.83) for the group with normomagnesemia and normocalcemia, 22.59 (95%CI: 21.94–23.24) and 5.16 (95%CI: 4.77–5.54) for the group with hypomagnesemia, 19.53 (95%CI: 18.36–20.70) and 4.52 (95%CI: 3.83–5.21) for the group with hypocalcemia, and 21.14 (95%CI 19.99–22.29) and 4.28 (95%CI 3.61–4.95) for the group with both hypomagnesemia and hypocalcemia, respectively. Magnesium and calcium deficiencies contributed to MMSE and CDT variance in the general linear models. Conclusions: Our findings indicate that in addition to age, body mass index, and chronic heart failure, both hypomagnesemia and hypocalcemia are associated with reduced cognitive performance. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the influence of wine, beer, and spirits consumption, respectively, on non-pathological, age-related cognitive decline from young adulthood to late midlife in a large follow-up study of Danish men. Methods: The study includes 2456 middle-aged Danish men from the Lifestyle and Cognition Follow-up study 2015, with information on adult-life consumption (from age 26) of wine, beer, and spirits self-reported in late midlife and age-related cognitive decline assessed using the same validated intelligence test administered in young adulthood and late midlife. Associations were adjusted for consumption of other alcoholic beverages, year of birth, age at follow-up, retest interval, education, young adulthood intelligence, and personality. Results: Most of the men had wine (48%) or beer (42%) as their preferred beverage type. For all three alcoholic beverages, consumption of more than 14 units weekly was associated with a greater decline in unadjusted analyses, but this trend was only significant for wine. In contrast, adjusted models showed that moderate wine and spirits consumption was associated with less decline than abstention for these alcohol types (p = 0.03 for 8–14 units/week of wine and p = 0.03 for 1–7 units/week of spirits). Statistical tests suggested a difference between the estimated effects of consumption of 8–14 units/week of wine and beer on cognitive decline. Conclusions: While patterns of associations were similar across beverages, moderate wine and spirits consumption may mitigate cognitive decline, in contrast with beer. However, the results should be interpreted with caution due to inherent differences between men with different alcoholic beverage preferences. [ABSTRACT FROM AUTHOR]

Background and Objectives Previous systemic reviews, predominantly including observational studies, have shown that participation in social activities is a protective factor against cognitive decline. However, this association is subject to potential reverse causality, creating a knowledge gap in our understanding of the effect of social interaction interventions on cognitive function. Therefore, this study aims to conduct a systematic review and meta-analysis of randomized controlled trials to examine the effects of social interaction interventions on cognitive decline among older adults without dementia. Research Design and Methods This systematic review, registered in PROSPERO (CRD42022367828), systematically searched 6 databases from inception to May 6, 2022, to identify relevant articles on the effects of activities with social interaction components on cognitive function in community-dwelling older adults without dementia aged above 60. Two independent reviewers conducted study selection, data extraction, and bias assessment, with RevMan5.3 used for meta-analysis. Subgroup analysis was conducted to assess variation in intervention effects among subgroups. Results We included 11 studies for qualitative analysis and 8 studies for the meta-analysis. The results showed that social interaction intervention had a significant effect on executive function (standardized mean difference [SMD] = 1.60; 95% CI, 0.50 to 2.70; p  = .004), but not attention and memory. The subgroup analysis showed a greater cognitive benefit for healthy older adults, but not those with mild cognitive impairment. Moreover, in-person social interaction positively affected global cognition, whereas online interaction did not. Discussion and Implications Social interaction interventions have a limited impact on cognitive function in older adults without dementia but showed potential effects on executive function. This finding offers insights for implementing social intervention in the community. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, which are characterized by progressive neuronal loss and cognitive decline, are a significant concern for the aging population. Neuroinflammation, a shared characteristic of these diseases, is implicated in their pathogenesis. This article briefly summarizes the role of magnesium, an essential mineral involved in numerous enzymatic reactions and critical for neuronal bioactivity, in the context of neuroinflammation and cognitive decline. The potential neuroprotective effects of magnesium, including the mechanisms of neuroprotection by magnesium through maintaining neuronal ion homeostasis, reducing inflammation, and preventing excitotoxicity, are also described. Additionally, we discuss the impact of inadequate magnesium on neuroinflammation and its potential as a therapeutic agent for attenuating cognitive decline to improve neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

The rising burden of dementia calls for high‐quality data on cognitive decline and dementia onset. The second wave of the Harmonized Diagnostic Assessment for the Longitudinal Aging Study in India (LASI‐DAD) was designed to provide longitudinal assessments of cognition and dementia in India. All Wave 1 participants were recruited for a follow‐up interview, and a refresher sample was drawn from the Longitudinal Aging Study in India, a nationally representative cohort of Indians aged 45 and older. Respondents underwent a battery of cognitive tests, geriatric assessments, and venous blood collection. Their health and cognitive status were also assessed through an interview with a close family member or friend. Clinical consensus diagnosis was made based on the Clinical Dementia Rating®, and comprehensive data on risk factors of dementia were collected, including neurodegenerative biomarkers, sensory function, and environmental exposures. A total of 4635 participants were recruited between 2022 and 2024 from 22 states and union territories of India, accounting for 97.9% of the population in India. The response rate was 84.0%, and 71.5% of the participants provided venous blood specimen. LASI‐DAD provides rich new data to study cognition, dementia, and their risk factors longitudinally in a nationally representative sample of older adults in India. Longitudinal cognitive data, together with longitudinally assessed biomarker data and novel data on sensory function and environmental exposures, provide a unique opportunity to establish associations between risk factors and biologically defined cognitive aging phenotypes. [ABSTRACT FROM AUTHOR]

Background: Inflammation significantly impacts Parkinson's disease (PD), yet the intricate relationship between inflammatory markers and PD remains elusive. Objective: To identify the peripheral biomarkers of PD and its correlation with the motor and non-motor symptoms of PD. Methods: 79 PD patients and 65 controls were included in this study. Clinical information and the serum levels of IL-8, IL-27, IL-33, β-NGF, AgRP, and TRAILR2 in the participants were collected. Appropriate scales were used to assess the symptoms of PD. For the factors with significant differences in the two groups, multivariable logistic regression was used to determine its relationship with PD. Moreover, spearman correlation was conducted to explore the correlation between the factors and PD related symptoms. The IL-27 level was compared between the cognitively healthy PD group and the mild cognitive impairment in PD (PD-MCI). The serum level of TRAILR2 was positively correlated with age and was not associated with other clinical characteristics related to PD. Results: Compared to controls, the serum levels of IL-27(P = 0.013) were increased whereas the levels of TRAILR2(P = 0.008) were decreased in PD patients. IL-8, IL-33, β-NGF, and AgRP showed no significant differences between the two groups. After controlling for the other variables, IL-27 was considered as an independent risk factor for PD in the multivariable logistic regression model. The receiver operating characteristic (ROC) curve for diagnosing PD with IL-27 yielded an area under the curve (AUC) of 0.621. Additionally, IL-27 level in PD patients was positively correlated with age, the disease duration, LEDD and negatively correlated with the MoCA scores. However, no significant difference was found in IL-27 levels between cognitively healthy PD and PD-MCI groups. Conclusion: Elevated serum IL-27 was a risk factor for PD and positively correlated with the cognitive decline in PD. [ABSTRACT FROM AUTHOR]

Age-related cognitive decline has become an increasingly relevant public health issue. However, risk and protective factors of cognitive decline have yet to be investigated prospectively taking into account genetic, lifestyle, physical and mental health factors. Population-based data from middle-aged (40 to 59 years; N = 2,764) and older individuals (60 to 80 years; N = 1,254) were drawn from a prospective community cohort study using the Tower of London (TOL) planning task. Assessments were repeated at a 5-year interval to investigate age-related changes in planning performance and to determine the impact of risk and protective factors. Planning performance improved in middle-aged, but declined in older participants over 5 years. SNPs affecting the dopamine system (COMT, DRD2) and APOE polymorphisms differentially predicted cognitive performance in older vs. middle-aged individuals. For older individuals, high alcohol consumption, antidepressant medication and living without a partner had additional negative predictive power on cognition. In contrast, undiagnosed hypertension, no obstructive lung disease, and fewer years of education predicted cognitive decline in the middle-aged group. The results inform screening for individuals particularly vulnerable to cognitive decline and interventions (e.g., focusing on lifestyle factors) to help maintain cognitive performance into old age. [ABSTRACT FROM AUTHOR]

Computerized training platforms could be an accessible means for older adults to maintain cognitive health, and several such tools are already commercially available. However, it remains unclear whether older adults use these tools if training is not externally prescribed. We explored older adults’ self-initiated experiences with cognitive training. We conducted semi-structured interviews with 13 community-dwelling adults aged 58–85 years, comprising university retirees (N = 8) and public housing residents (N = 5). Interviews were analyzed by thematic analysis. No participants voluntarily used cognitive training, and those who had done so previously reported negative experiences. Several factors shaped older adults’ engagement with cognitive training, especially a preference for stimulating activities that are organic and inherently enjoyable. We reveal a mismatch between older adults’ priorities and the interventions currently available and uncover issues of access and interest among low-income and minority individuals. We suggest ways to better align future interventions with older adults’ priorities. [ABSTRACT FROM AUTHOR]

Background: Previous research has indicated that engagement in social activities has proven advantageous for diminishing the likelihood of cognitive decline. However, no study has examined whether such cognitive benefits were to a similar extent for the young-old, the old-old, and the oldest-old groups. The purpose of this research was to determine whether aging would have an impact on the changes in cognitive function that would occur in older adults with varying degrees of social involvement. Methods: The sample for this study comprised 4,481 older adults who participated in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) during the waves spanning from 2008 to 2018. At baseline, participants were classified into the young-old (60-69 years; Mage = 66.66; SD = 1.87), the old-old (70-79 years; Mage = 74.21; SD = 2.82), and the oldest-old (80 years or older; Mage = 86.46; SD = 5.71) groups. Results: The level of cognitive function decreased as participants aged. Importantly, compared to those lacking social activities, individuals who were got involved in social engagement at baseline had slower rates of cognitive decline over time. Furthermore, compared with the young-old group and the old-old group, the impact of social activity engagement on slowing cognitive decline was more salient for the oldest-old group. Conclusion: Active engagement in social activities can slow age-related cognitive decline, particularly for the oldest-old group. To preserve cognitive function with aging, attention and resources should be allocated to encourage social activity engagement. [ABSTRACT FROM AUTHOR]

Objectives: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder lacking reliable neuroimaging biomarkers. This study aimed to evaluate microstructural and functional connectivity alterations using diffusion kurtosis imaging (DKI) and resting-state fMRI (rs-fMRI), and to investigate their diagnostic potential as biomarkers. Methods: Twenty-three patients with NIID and 40 matched healthy controls (HCs) were recruited. Firstly, gray matter (GM) and white matter (WM) changes were assessed by voxel-based analysis (VBA) and tract-based spatial statistics (TBSS). Then we explored modifications in brain functional networks connectivity by independent component analysis. And the relationship between the altered DKI parameters and neuropsychological evaluation was analyzed. Finally, a receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of different gray matter and white matter parameters. Results: Compared with the HCs, NIID patients showed reduced mean kurtosis (MK), radial kurtosis (RK), axial kurtosis (AK), and kurtosis fractional anisotropy (KFA) values in deep gray matter regions. Significantly decreased MK, RK, AK, KFA and fractional anisotropy (FA), and increased mean diffusivity (MD) values were observed in extensive white matter fiber tracts. Notable alterations in functional connectivity were also detected. Among all DKI parameters, the diagnostic efficiency of AK in GM and FA in WM regions was the highest. Conclusion: Adult-onset NIID patients exhibited altered microstructure and functional network connectivity. Our findings suggest that DKI parameters may serve as potential imaging biomarkers for diagnosing adult-onset NIID. [ABSTRACT FROM AUTHOR]

Iron overload causes cognitive impairment in thalassemia patients. The gut-brain axis plays an important role in cognitive function. However, the association between gut/blood microbiome, cognition, and iron burden in thalassemia patients has not been thoroughly investigated. We aimed to determine those associations in thalassemia patients with different blood-transfusion regimens. Sixty participants: healthy controls, transfusion-dependent thalassemia (TDT) patients, and non-transfusion-dependent (NTDT) patients, were recruited to evaluate iron overload, cognition, and gut/blood microbiome. TDT patients exhibited greater iron overload than NTDT patients. Most thalassemia patients developed gut dysbiosis, and approximately 25% of the patients developed minor cognitive impairment. Increased Fusobacteriota and Verrucomicrobiota with decreased Fibrobacterota were observed in both TDT and NTDT groups. TDT patients showed more abundant beneficial bacteria: Verrucomicrobia. Iron overload was correlated with cognitive impairment. Increased Butyricimonas and decreased Paraclostridium were associated with higher cognitive function. No trace of blood microbiota was observed. Differences in blood bacterial profiles of thalassemia patients and controls were insignificant. These findings suggest iron overload plays a role in the imbalance of gut microbiota and impaired cognitive function in thalassemia patients. Harnessing probiotic potential from those microbes could prevent the gut-brain disturbance in thalassemia patients. [ABSTRACT FROM AUTHOR]

Loneliness and associated physical and cognitive health decline among the aging population is an important medical concern, exacerbated in times of abnormal isolation like the 2020–2021 Covid-19 pandemic lockdown. In this backdrop, recent "social prescribing" based health policy initiatives such as community groups as a support structure for the aging population assumes great importance. In this paper, we evaluate and quantify the impact of such social prescribing policies in combatting loneliness and related health degeneration of the aging population in times of abnormal isolation. To this end, we conduct a natural experiment across a sample of 618 individuals aged 65 and over with varying access to community groups during the Covid-19 lockdown period. Using a random-effects, probit model to compare the differences in health outcomes of participants with access to community groups (target) with those without access (control), we find that the target group was 2.65 times less likely to suffer from loneliness as compared to the control group, along with lower incidences of reported cardiovascular and cognitive health decline. These initial findings provide preliminary support in favor of the interventional power of social prescription tools in mitigating loneliness and its consequent negative health impact on the aging population. [ABSTRACT FROM AUTHOR]

Background: Analysis of selected research cohorts has highlighted an association between plasma neurofilament light (NfL) protein and cross-sectional cognitive impairment as well as longitudinal cognitive decline. However, the findings have yielded inconsistent results regarding its possible application in clinical practice. Despite its potential prognostic significance, the role of plasma NfL in daily clinical practice with unselected patients suffering from cognitive impairment remains largely unexplored. Methods: This retrospective, cross-sectional and longitudinal monocentric study enrolled 320 patients with Alzheimer's disease ([AD], n = 158), dementia with Lewy body ([DLB], n = 30), frontotemporal dementia ([FTD], n = 32), non-neurodegenerative diseases ([NND], n = 59) or subjective cognitive decline ([SCD], n = 41). Plasma NfL levels were measured at baseline on the Simoa platform. AD, DLB, and FTD patients were also analyzed altogether as a 'degenerative conditions' subgroup, whereas SCD and NND were grouped as a 'non-degenerative conditions' subgroup. We assessed the relationship between plasma NfL levels and cross-sectional cognitive performance, including global cognition and six specific cognitive domains. A subset of 239 patients had follow-up mini-mental state examinations (MMSE) up to 60 months. Models were adjusted on age, education level, glomerular filtration rate and body mass index. Results: In 320 patients, baseline plasma NfL levels were negatively associated with global cognition (β=-1.28 (-1.81 ; -0.75) P < 0.001), memory (β=-1.48 (-2.38 ; -0.59), P = 0.001), language (β=-1.72(-2.49 ; -0.95) P < 0.001), praxis (β=-2.02 (-2.91 ; -1.13) P < 0.001) and executive functions (β=-0.81, P < 0.001). Across diagnosis, plasma NfL levels were negatively associated with cross-sectional global cognition in all but the SCD subgroup, specifically with executive functions and memory in AD (respectively β=-0.71(-1.21 ; -0.211), P = 0.005 and β=-1.29 (-2.17 ; -0.42), P = 0.004), and with attention in LBD (β=-0.81(-1.16 ; -0.002), P = 0.03). Linear mixed-effects models showed that plasma NfL predicted MMSE decline in the global population (βPlasmaNfLxTime=-0.15 (-0.26 ; -0.04), P = 0.006), as in the neurodegenerative condition subgroup (βPlasmaNfLxTime=-0.21 (-0.37 ; − 0.06), P = 0.007), but not in non-neurodegenerative condition subgroup. Conclusion: In our clinical cohort, plasma NfL was associated with faster cognitive decline in neurodegenerative dementia, which corroborates data obtained in research cohorts. Yet, plasma NfL was not predictive of accelerated cognitive decline in individuals without neurodegeneration, suggesting its use as a neurodegeneration-specific predictive biomarker. [ABSTRACT FROM AUTHOR]

Background: Arterial stiffness is a degenerative modification in the arterial wall that significantly affects normal aging. Arterial hypertension is a major risk factor for cerebrovascular impairment. Pulse wave velocity (PWV) is an established gold standard for measuring arterial stiffness. Studies demonstrated that individuals with elevated blood pressure (BP) and PWV are more likely to experience worse cognitive decline compared to those with either condition alone. The aim of this review is to explore the clinical importance of arterial stiffness for cognitive function in older adults with hypertension. Methods: The systematic review was reported following the PRISMA 2020 guidelines and Cochrane protocol and was registered in NIHR PROSPERO. PubMed, Embase, Web of Science, CINAHL, and Cochrane databases were searched for relevant publications up to December 2022. Articles were filtered by age and type of study and only those including a sample size of at least 500 individuals were selected. Screening of abstracts and full-text review of selected articles were carried out through Covidence. Results: The full-text review included a total of 434 articles. Twenty-eight prospective studies have met the inclusion criteria. Selected studies used PWV as the main measurement of stiffness: 24 used carotid-femoral, 2 used brachial-ankle, 1 used aortic PWV, and 11 compared different measures. Studies demonstrated a strong association between increased BP and PWV with brain damage and cognitive deterioration among older adults. One study did not find an interaction with hypertension, while another study found that PWV but not BP was associated with cognitive decline. Few studies showed that the association between stiffness and cognitive outcomes was not significant after adjustment for BP. Several authors suggested that cognitive decline induced by stiff vasculature and hypertension benefited from antihypertensive therapy. Conclusion: The results of this review demonstrated that arterial hypertension is an important factor linking arterial stiffness to cognitive health in older individuals. BP plays a crucial role in brain integrity, whereas PWV was shown to be a strong measure associated with cognitive decline. Together, they can lead to disabling cognitive outcomes. Early screening of stiffness, BP control, and compliance with treatment are essential for cerebrovascular disease prevention. Trial registration: NIHR PROSPERO registry ID: CRD42022379887. [ABSTRACT FROM AUTHOR]

Haploinsufficiency of the transcriptional repressor ZBTB18/RP58 is associated with intellectual disability. However, the mechanisms causing this disability are unknown, and preventative measures and treatments are not available. Here, we assessed multiple behaviors in Zbtb18/Rp58 heterozygous-knockout mice, and examined local field potentials, DNA fragmentation, mitochondrial morphology, and performed histochemical and transcriptome analyses in the hippocampus to evaluate chronic inflammation. In wild-type mice, object location memory was present at a similar level at 2 and 4–5 months of age, and became impaired at 12–18 months. In contrast, Zbtb18/Rp58 heterozygous-knockout mice displayed early onset impairments in object location memory by 4–5 months of age. These mice also exhibited earlier accumulation of DNA and mitochondrial damage, and activated microglia in the dentate gyrus, which are associated with defective DNA repair. Notably, chronic minocycline therapy, which has neuroprotective and anti-inflammatory effects, attenuated age-related phenotypes, including accumulation of DNA damage, increased microglial activation, and impairment of object location memory. Our results suggest that Zbtb18/Rp58 activity is required for DNA repair and its reduction results in DNA and mitochondrial damage, increased activation of microglia, and inflammation, leading to accelerated declines in cognitive functions. Minocycline has potential as a therapeutic agent for the treatment of ZBTB18/RP58 haploinsufficiency-associated cognitive dysfunction. [ABSTRACT FROM AUTHOR]

This systematic literature review aims to answer the question of how micronutrients might influence the development and progression of dementia. In the present work, we focused on an overview of an updated review of relevant literature published in the last two decades. This review aims to delineate the relationship between micronutrient supplementation and cognitive decline in older subjects. In carrying out this review, we followed PRISMA, and our literature search was performed on PubMed. This systematic review includes only primary studies that have investigated the efficacy of nutritional interventions for the prevention of dementia and improvement of cognitive function in subjects aged 65 years or older with normal cognition, mild cognitive impairment (MCI), or Alzheimer's disease (AD). A gross heterogeneity of studies forbids the possibility of a direct comparison of the results. A review of the inclusion criteria and restrictions has been conducted to check the validity and reliability of the results. In this review, thirty-three primary studies were included. Results have shown that supplementation with vitamin D, probiotics, and PUFAs would most likely reduce cognitive decline, dementia, or AD compared with vitamins A, B, C, and E, which were seen to be relatively ineffective. Of note, when considering vitamin B supplementation, positive effects were only observed in non-aspirin users having high ω-3 fatty acid (ω-3 FA) plasma levels. In some cases, however, there were genotypic differences in subjects in response to vitamin B supplementation. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) is a common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a novel transgenic rat model (rTg-D) that produces human familial CAA Dutch E22Q mutant amyloid β-protein (Aβ) in brain and develops arteriolar CAA type-2. Here, we show that deposition of fibrillar Aβ promotes arteriolar smooth muscle cell loss and cerebral microhemorrhages that can be detected by magnetic resonance imaging and confirmed by histopathology. Aged rTg-D rats also present with cognitive deficits. Cerebral proteomic analyses revealed 241 proteins that were significantly elevated with an increase of >50% in rTg-D rats presenting with CAA compared to wild-type rats. Fewer proteins were significantly decreased in rTg-D rats. Of note, high temperature requirement peptidase A (HTRA1), a proteinase linked to transforming growth factor beta 1 (TGF-β1) signaling, was elevated and found to accumulate in cerebral vessels harboring amyloid deposits. Pathway analysis indicated elevation of the TGF-β1 pathway and increased TGF-β1 levels were detected in rTg-D rats. In conclusion, the present findings provide new molecular insights into the pathogenesis of CAA and suggest a role for interactions between HTRA1 and TGF-β1 in the disease process. [ABSTRACT FROM AUTHOR]

Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age‐associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence‐associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging. [ABSTRACT FROM AUTHOR]

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes mellitus (T2DM) over time predisposes to inflammatory responses and abnormalities in functional brain networks that damage learning, memory, or executive function. The hippocampus is a key region often reporting connectivity abnormalities in memory disorders. Here, we investigated peripheral inflammatory responses and resting-state functional connectivity (RSFC) changes characterized of hippocampal subregions in type 2 diabetes-associated cognitive decline (T2DACD). Methods: The study included 16 patients with T2DM, 16 patients with T2DACD and 25 healthy controls (HCs). Subjects were assessed for cognitive performance, tested for the expression of inflammatory factors IL-6, IL-10 and TNF-α in peripheral serum, underwent resting-state functional magnetic resonance imaging scans, and analyzed for RSFC using the hippocampal subregions as seeds. We also calculated the correlation between cognitive performance and RSFC of hippocampal subregion, and analyzed the significantly altered RSFC values of T2DACD for Receiver Operating Characteristic (ROC) analysis. Results: T2DACD patients showed a decline in their ability to complete cognitive assessment scales and experimental paradigms, and T2DM did not show abnormal cognitive performance. IL-6 expression was increased in peripheral serum in both T2DACD and T2DM. Compared with HCs, T2DACD showed abnormalities RSFC of the left anterior hippocampus with left precentral gyrus and left angular gyrus. T2DM showed abnormalities RSFC of the left middle hippocampus with right medial frontal gyrus, right anterior and middle hippocampus with left precuneus, left anterior hippocampus with right precuneus and right posterior middle temporal gyrus. Compared with T2DM, T2DACD showed abnormalities RSFC of the left posterior hippocampus and right middle hippocampus with left precuneus. In addition, RSFC in the left posterior hippocampus with left precuneus of T2DACD was positively correlated with Flanker conflict response time (r=0.766, P=0.001). In the ROC analysis, the significantly altered RSFC values of T2DACD achieved significant performance. Conclusions: T2DACD showed a significant decrease in attentional inhibition and working memory, peripheral pro-inflammatory response increased, and abnormalities RSFC of the hippocampal subregions with default mode network and sensory-motor network. T2DM did not show a significant cognitive decline, but peripheral pro-inflammatory response increased and abnormalities RSFC of the hippocampus subregions occurred in the brain. In addition, the left precuneus may be a key brain region in the conversion of T2DM to T2DACD. The results of this study may provide a basis for the preliminary diagnosis of T2DACD. [ABSTRACT FROM AUTHOR]

In the central nervous system, oligodendrocytes wrap around neuronal axons to form myelin, an insulating layer or sheath that allows for the efficient conductance of action potentials. In addition to structural insulation, myelin provides encased axons with nutrient, metabolic and defensive support. Demyelination, or myelin loss, can therefore cause axonal dysfunction, leading to neurological impairment and disease. In Alzheimer’s disease (AD), progressive white matter demyelination is acknowledged as one of the earliest pathologies preceding symptom onset. Unfortunately, current pharmacotherapy for slowing demyelination or promoting remyelination in AD is nonexistent. Exercise is recognized for its wide-ranging benefits to human health, including improved mental health and the prevention of lifestyle-related diseases. Mounting evidence suggests the contribution of physical activity in delaying the progression of dementia in elderly populations. Recent mechanistic studies have shown that exercise facilitates myelination in the brain through the vitalization of intrinsic pro-myelination cues, such as increased neurotrophic factors and electrical activity. In this review, we summarize and discuss the potential of physical exercise on counteracting aging-associated white matter demyelination, which causes cognitive decline in AD. We highlight the need of further basic and clinical research investigations on this topic to establish novel approaches for healthy and improved brain aging. [ABSTRACT FROM AUTHOR]

Type-2 diabetes is associated with an increased risk of dementia, and the underlying mechanism might involve abnormal insulin signaling in the brain. The objective of this study was to examine the association of postmortem brain insulin signaling with late-life cognitive decline. Among participants of Religious Orders Study, a community-based clinical-pathological cohort, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had postmortem brain insulin signaling measurements collected in the prefrontal cortex using ELISA and immunohistochemistry. By using adjusted linear mixed-effects models, we examined the association of postmortem brain insulin signaling with late-life cognitive function assessed longitudinally (mean follow-up duration = 9.4 years) using a battery of neuropsychological tests. We found that a higher level of serine/threonine-protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) was associated with a faster decline in global cognition (estimate = - 0.023, p = 0.030), and three domains: episodic memory (estimate = -0.024, p = 0.032), working memory (estimate = -0.018, p = 0.012), and visuospatial abilities (estimate = -0.013, p = 0.027). The level of insulin receptor substrate-1 (IRS1) phosphorylation (pS307IRS1/total IRS1) was not associated with decline in global cognition or most cognitive domains, except for perceptual speed (estimate = 0.020, p = 0.020). The density of pS616IRS1- stained cells was not associated with decline in global cognition or any of the domains. In conclusion, these findings provide novel evidence for an association between brain insulin signaling and late-life cognitive decline. AKT phosphorylation is associated with a decline in global cognition and memory in particular, whereas IRS1 phosphorylation is associated with a decline in perceptual speed. [ABSTRACT FROM AUTHOR]

Background: Persistent pain is a prominent symptom of knee osteoarthritis (KOA) and has been associated with cognitive decline in individuals with KOA. The amygdala, a complex structure consisting of nine subnuclei, and programmed cell death protein‐1 (PD‐1) levels play crucial roles in pain regulation and cognitive processing. This study aims to investigate the relationships among amygdala subregion volumes, cognitive function, and PD‐1 levels to elucidate the underlying mechanism of cognitive decline in KOA. Methods: In this cross‐sectional study, we recruited 36 patients with KOA and 25 age/gender‐matched healthy controls for neuropsychological tests, structural magnetic resonance imaging scanning, and measurement of serum PD‐1 levels. We used the atlas provided by FreeSurfer software to automatically segment the amygdala subnuclei. Subsequently, we compared the volumes of amygdala subregions between groups and explored their correlation with clinical scores and PD‐1 levels. Results: Compared to healthy controls, individuals with KOA exhibited significantly lower scores on global cognition tasks, such as long‐delay free recall, short‐delay free recall, and immediate recall tasks. Moreover, they displayed decreased volumes in lateral nucleus basal nucleus paralaminar nucleus while showing increased volumes in accessory basal nucleus, central nucleus, medial nucleus, and cortical nucleus. Within the KOA group specifically, paralaminar volume was negatively correlated with immediate recall scores; pain scores were negatively correlated with global cognition; basal volume was negatively correlated with PD‐1 levels. Conclusion: Our findings highlight those alterations in amygdala subregion volumes along with changes in serum PD‐1 levels may contribute to observe cognitive decline among individuals suffering from KOA. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of different intensities of physical activity (PA) on cognitive function in middle-aged and elderly individuals, and to predict future trends in cognitive ability using longitudinal data to assess the long-term role of PA in cognitive preservation. Methods: Data from the China Health and Retirement Longitudinal Study (CHARLS) were utilized. Mixed-effects models were employed to analyze the impacts of low-intensity PA (LPA), moderate-intensity PA (MPA), and vigorous-intensity PA (VPA) on overall cognition, episodic memory, and mental intactness. Random forest and XGBoost machine learning methods were employed to further validate the effects of PA. ARIMA models predicted future cognitive trends under the influence of PA. Results: MPA demonstrated significant advantages in preserving cognitive function, particularly in overall cognition and episodic memory. While LPA had some protective effects, they were less significant than those of MPA, and VPA did not show advantages. Machine learning methods confirmed these findings. ARIMA model predictions indicated that the protective effects of MPA on cognitive function are likely to persist in the future. Conclusions: Moderate-intensity physical activity is associated with the preservation of cognitive ability in middle-aged and elderly individuals and may continue to provide this benefit in the future; however, further in-depth research is needed for confirmation. [ABSTRACT FROM AUTHOR]

Cognitive decline is a public health concern affecting about 50 million individuals worldwide. Neuroticism, defined as the trait disposition to experience intense and frequent negative emotions, has been associated with an increased risk of late-life cognitive decline. However, the underlying biological mechanisms of this association remain unknown. This study investigated the relationship between genetic predisposition to neuroticism, computed by polygenic risk score (PRS), and performance in cognitive domains of reasoning, processing speed, visual attention, and memory in individuals over age 60. The sample consisted of UK Biobank participants with genetic and cognitive data available (N = 10,737, 4686 females; mean age = 63.4 ± 2.71). The cognitive domains were assessed at baseline for all participants and seven years later for a subset (N = 645, 262 females; mean age = 62.9 ± 2.44). Neuroticism PRS was not associated cross-sectionally with cognitive measures (p > 0.05). However, the trajectory of change for processing speed (β = 0.020; 95% CI = [0.006, 0.035], adjusted p = 0.0148), visual attention (β = −0.077; 95% CI = [−0.0985, −0.0553], adjusted p = 1.412 × 10−11), and memory (β = −0.033; 95% CI = [−0.0535, −0.0131], adjusted p = 0.005) was significantly associated with neuroticism PRS. Specifically, a higher genetic predisposition to neuroticism was associated with less decline in these cognitive domains. This trend persisted after sensitivity analysis using complete cases, although it only remained nominally significant for visual attention. [ABSTRACT FROM AUTHOR]